Inflammatory Pyramid

 

Cytokines:

Cytokines are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. Their release has an effect on the behavior of cells around them. It can be said that cytokines are involved in autocrine signaling, paracrine signaling and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines may include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors but generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell. They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-biased immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in less variable concentrations and hormones tend to be made by specific kinds of cells.

They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

 

 

On first glance, the normal crystal clear appearance of the Cornea looks like a fairly simple process. In reality maintainence of a clear cornea is a highly complex process involving the nervous system, immune modulators, and a host of factors which need to be interacting in a very precise fashion. Disruption of the Corneal surface either from dryness or other factors triggers a variety of immune, cellular and neural reactions which need to be stabilized to re-establish the crystal clear appearance of the cornea we often take for granted.

Only recently has the importance of cellular immune modulators been identified as well as their interaction with neural and other factors such as the release of T-cells, death of cells on the corneal surface precipitating even more cytokine release.

Pyramid Explanations:

Lid Margin Treatment: Debris can build up on the lid margins which include dead glandular tissue, debris on the lashes[collarettes] dead bacteria and occasional parasites that occupy the glands. All this debris can mingle with and adversely affect the tear film. A number of methods exist for cleaning the lids and lashes. Warm compresses with various antibiotic components are frequently effective but must be used on a regular basis to be effective.. Plugged gland openings and some lid debris and can be very tenacious and difficult to remove. Mechanical debridement routinely done by a trained technician or physician can remove this debris but hot packs are frequently necessary to completely remove debris. Lipiflow which uses heat and pulsation has been proven to alleviate this condition and to rehabilitate the meibomian glands and consequently maintain a healthy tear film.

Tear replacements: Numerous products exist to replace tears in evaporative tear loss. They vary in viscosity[thickness], saline content, and some contain lubricating molecules of varying kinds. The main problem with reusable artificial tears is they are required to not only be sterile but they also must be self-sterilizing in that exposure to bacteria or viruses or other pathogens will be killed on contact. In addition, all eye drops require preservatives to maintain the effectiveness of the medication over its shelf life.

All these additives add nothing to the lubricating quality of artificial tears. When used frequently the non-lubricating contents especially one BAk[Benzylkonium Chloride] is irritating and even more irritating when drops are used frequently.

Many pharmaceutical companies also supply non preserved tears in individual one use dispensers. If handled carefully they can sometimes be used safely more than once but the risk of contamination is real. On a related note, I have frequently come across contact lens wearers who complain of irritation. I discovered they rarely if ever cleaned their contact lens soaking solution containers. When I cultured the contents of their contact lens cases I found all sort of pathogens that no doubt was inhabiting their lenses. I was surprised that though they occasionally developed a corneal infection, that these infections weren’t more frequent. The take home message from this is that healthy tears actively kill a variety of potentially sight threatening pathogens and give further evidence for the need of a healthy tear film.

Cyclodporin A is the compound in the drug Restasis. In much larger quantities Cyclosporin A is a key medication in patients with lung or kidney transplants which prevent rejection of the transplanted organ. In an eye drop formulation in very small concentrations[solubized in peanut oil] restasis can be highly effective in treating a variety of dry eye patients. Surprising after prescribing Restasis for 20 years, the only ill effects I have encountered are minor irritations from the peanut oil vehicle which can be relieved by a short course of steroid drops.

Androgens are only of value [in my experience] in Androgen deficient patients. Theories on why Dry eye is more common in post menopausal women are are attributed to the fact that some of estrogen’s metabolic breakdown products are actually male androgens[testosterone]. It appears that some level of these androgenic substances is necessary for proper tear secretion levels. So far no medication for dry eye has been produced that addresses this issue.

Systemic antinflammatories: Generally these medication have little effect on dry eye. However in some auto immune diseases like Lupus and Rheumatoid Arthritis , NSAIDS, non steroidal anti-inflammatories[Ibuprofen, celexcib, naproxen etc] help the overall disease complex and maybe beneficial to the patient in other ways.

Systemic antibiotics: Some medications in the tetracycline family, Doxycycline and minocycline are very useful especially in posterior[effecting lid glands] Blepharitis. These drugs as well as some other antibiotics of different classes appear to not only treat the infectious process but seem to benefit the tear film in ways not clearly understood

Topical antibiotics: topical antibiotics in both drop and ointment form can keep bacterial blepharitis under control . one medication Zithromax drops[same medication as in Z-pacs] marketed as Azasite appears to be capable of penetrating clogged lid glands and have been found to be very useful even after very short[2 days] treatment periods. Unfortunately Zithromax and some of the newer topical antibiotic drops are very expensive. Consequently when possible most Ophthalmologists will use less expensive medications such as bacitracin ointment for long term management of chronic lid infection. Neomycin ointment in combination with other antibiotics are often inexpensive substitutes. However Neomycin[a drug like gentamicin and tobramycin are in the aminoglycoside family]. A significant fraction of patients develop a toxic/allergic reaction to these medications especially when used over weeks or months. I try to avoid long term use of these medication. It is not uncommon for me to get a call on a Friday afternoon from a non-Ophthalmologist who relates to be me how he treated a putative infection with neomycin, switched to gentamicin or tobramycin and the infection only got worse. Invariably this is a reaction to the aminoglycoside compound and is easily diagnosed by asking the patient to look up and the inferior cul de sac of the conjunctiva is beet red while when looking down the superior conjunctiva is white and quiet. This happens so often I have stopped taking pictures and simply discontinue medication , sometimes adding a steroid drop to reduce discomfort. The reason for the eye appearance in these cases is that topical drops accumulate in the inferior cul de sac and gravity keeps them there increasing the toxicity.

Mucolytics such as N-acetyl cysteine were once used to treat dry eye but have been replaced virtually completely by Restasis and Xiidra.

Xiidra is the latest medication shown to be of value in treating dry eye the mechanism involves interrupting the inflammatory pathway which leads to corneal inflammation. A video on this website describes the action far better than a written description. The use of Xiidra alone or in combination with other medications is currently under active investigation but there is no doubt it is highly effective in selected patients. I am still learning from my patients how to best use this new tool in our armamentarium for treating Dry Eye.

Autologous Serum is what is left when the blood is spun in a centrifuge and the red blood cells are separated from the remainder of the blood known as serum. When I first began my career as junior faculty at UC Irvine, My world famous mentor said “ you want to make your dry eye patients happy, spin down their blood. Take the serum in a dropper and put it in the eye. You will instantly be a hero” He was right but in the 50 years since that conversation, I haven’t seen a dry eye treatment based on this concept.

Omega 3 fatty acids: Many patients are on fish oil or flax seed oil which are high in omega 3s to lower their bad cholesterol LDLs and increase their good cholesterol HDLs. However Omega-3s , flax seed oil in my case, has been the most effective way to control my Dry eye. Everyone such probably be on omega 3s except those who develop abdominal problems when taking them. Part of the problem is the rules that govern OTC “nutraceuticals”. By law they must contain the product listed on the label. However the FDA does not oversee what other products[junk] can be present in the bottle. As a general rule, ask the pharmacist which are the better quality brands and as these products are relatively inexpensive, buy the better quality product. I have found in my patients, going with a slightly more expensive omega 3 will often reduce any gastrointestinal problems.

Therapeutic lenses: these lenses are reserved for only the most severe dry cases in my experience. I prefer to refer to a therapeutic contact lens fitter when confronted with patients who need some form of lens to maintain corneal integrity.

Neuro stim: attempts to reestablish the feedback loop whereby dryness stimulates tear production through a neural feedback loop. I have had little experience with this treatment and it is still investigatory and only used in University laboratory situations. I haven’t seen any recent article on it but it certainly has the potential to benefit patients where strokes or tumors have disrupted the normal neural tear feedback loop.

As I have stressed on this website, Dry eye and related conditions require an individualized approach and not a “cookbook” recipe to quickly and adequately address the problem and maintain a healthy tear film long term. This triangle diagram represents a treatment algorithm for inflammation-based dry eye and does not address other types of dry eye. I provided it as a guide to how decisions are made in dry eye treatment.

 

 

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